The primary objective of Project 5 is to screen a large number of non- peptide chemicals to identify molecules that can block receptors or enzymes specifically associated with HIV. The discovery of non-peptide, synthetic chemicals of small molecular weight which are substrate analogues to HIV-specific enzymes or which bind to T-cell membrane receptors could lead to promising drug candidates. Non-peptide drugs, compared with the peptide drugs currently under development (T-peptide, CD4 fragments, monoclonal antibodies), may have better pharmacokinetic properties, are likely to be less non-immunogenic, and may be less expensive to manufacture. The initial focus of Project 5 will be to screen for blockers of the CD4/gp120 interaction. Assays developed by other consortium groups (Projects 1-4) may be subsequently incorporated into the screening program. The key technology underlying the random or semi-directed screening of chemicals for use in AIDS therapy is a unique, highly automated, high throughput system for performing receptor binding assays. This system (NovaScreen) provides for rapid (hundreds of test chemicals/day) and cost-effective primary screening for lead compounds. The three initial steps in the screening strategy identify lead compounds in a rapid and cost-effective manner, culling out uninteresting compounds before any significant effort and expense is invested in development. Results on Phase I screening of up to 1,000 chemicals can be produced within 24 hr. Phase I Pass 2 serves to quickly confirm "hits" from the first screen by repeating the assay (three replicate tubes, test chemical at 10 uM). Promising compounds are moved into Phase II testing: concentration-response curves are performed for calculating a precise binding constant. Following the discovery of compounds with high affinity for the binding sites of interest, a complementary program of medicinal chemistry (within Project 5) and rational drug design (Group Project 4) will be undertaken. The objective of each approach will be to contribute structure-activity information of value to increasing potency and reducing side effects of lead compounds. At the same time, pre-clinical tests of the functional activity of lead compounds (e.g., potency for blocking HIV infectivity) and toxicity (whole-animal assays) will be undertaken.